Nitroarenes with carbanions

The 2,1 -benzisoxazole (anthranil) ring system is of interest as a key intermediate for the synthesis of other heterocycles. 2,1-Benzisoxazoles can be derived from the direct multistep domino reaction of some carbanions with nitroarenes or by conversion of the products of nucleophilic substitution of hydrogen in nitroarenes. As early as in 1960, Davis and Pizzini reported that the reaction of 4-chloronitrobenzene with phenylacetonitrile in the presence of potassium hydroxide in protic media affords 3-phenyl-5-chloro-2,l-benzisoxazole in high yield [80] (Scheme 17). 

Alkylation of carbanions of a-halogenomethyl sulphoxides enables one to elongate the alkyl chain403-406 (equations 175 and 176). a-Chlorosulphoxides react with nitroarenes in... 

The carbanion of 2,3-dimethylthiazolidine-4-one reacted with nitroarenes to give either a ting opened product (50) via a VNS (vicarious nucleophilic substitution) reaction or a product resulting from oxidative nucleophilic substitution of hydrogen (51). Ring opening VNS reactions with 5-membered 5-heterocycles are limited to those heterocycles which show some conformational flexibility <96TL983>. 

It was subsequently shown that carbanions generated from substituted a-chloroalkanenitriles [15] and alkyl a-chloroalkanoates [16, 17], chloroalkyl oxazolines [18, 19], chloroform [20], etc., although they are much less stable than the model sulfone carbanion, are able to react with nitroarenes to give the VNS products. 

The effect of substituents on the rate of addition of carbanions to nitroarenes and the rate of p-elimination of HL from the o adducts have also been studied [8, 30, 31]. The former effect is an important parameter, because it is, in fact, a measure of influence of substituents on electrophilic activity of nitroaromatic rings. The effect of substituents on rate of the S Ar reactions of o- and p-halonitrobenzenes has been thoroughly studied [2, 32]. However, since the S Ar of halogen is a secondary process, the obtained data cannot be used as a real measure of electrophilicity of halonitroarenes. We have determined the effects of substituents and the ring structure on the rate of the VNS reactimi of nitroarenes with the carbanion of chloromethyl phenyl sulfone by using competitive experiments under the conditions, which assure a fast p-eUmination of HL from the o adducts [30, 31]. The values of VNS rates obtained under such conditions proved to correlate with those of the addition step. Selected values of the relative rate constants in relation to nitrobenzene as the standard are shown in Fig. 1. 

There are numerous examples of construction of condensed pyridines (and also quinolines and acridines) via cascade reactions, involving conversion of the adducts of benzylic or allylic carbanions to nitroarenes followed by their intramolecular cyclization to form the pyridine ring. Thus, the reaction between 4-chloronitrobenzene and phenylacetonitrile, which is known to produce in protic media the corresponding 2,1-benzisoxazole via conversion of the intermediate adduct into nitrosoarene and its further condensation reaction [80], can proceed in aprotic media along another way. The same o adduct formed in tetrahydrofuran, when treated with trialkylchlorosilanes or pivaloyl chloride, undergoes cycUzatiOTi into acridine derivative (Scheme 85) [208]. 

On the other hand, when o -adducts of arylacetonitrile carbanions to para-substituted nitroarenes are converted into substituted nitrosoarenes in aprotic media via silylation in the presence of trialkylamines, the produced o-nitrosoaryl acetonitriles can undergo further hetero-cyclization on alternative pathway to produce substituted acridines [28]. Reactions of arylacetonitriles with nitroarenes unsubstituted in the para position under identical protic conditions result in the formation of p-nitrosoaryl arylacetonitriles that can be isolated in the tautomeric form of p-arylcyanomethylene quinone oximes (Scheme 11.13) [27b]. 

AllyUc carbanions, under conditions that promote conversion of the o -adducts into nitrosoarenes, react with nitroarenes to form a variety of heterocychc systems. For instance, carbanion of aUyl tolyl sulfone in the reaction with 2-nitrothiophene forms substituted pyridothiophene (Scheme 11.14) [29]. 

On the other hand, the VNS reaction of chloroform with nitroarenes carried out in the presence of t-BuOK that gives dichloromethyl nitroarenes [65] proceeds via addition of trichloromethyl carbanions to electrophihc aromatic rings of nitroarenes and formation of anionic intermediates [65]. One can therefore consider VNS as an umpolimg of the Friedel-Crafts reaction. It is also a process complementary to the Friedel-Crafts reaction, because it proceeds with nitroarenes that usually do not enter the Friedel-Crafts reaction (Scheme 11.41). 

Another pathway is displayed in Scheme 42. An acridine-9-carbonitrile (119) synthesis from carbanions and nitroarenes 117 followed by reductive transformation of the nitro group with sdylating or acylating agents can be regarded as a recent example of a type B or D ring closure, if the starting... 

The novel cyclizadon takes places by the silane-mediated condensadon of nitroarenes with allylic carbanions, in which a sLx-membered nitrogen-containing ting is constnicted fEq. 9.54. ... 

The foregoing examples show that the nucleophilic attack to nitroarenes at theorr/io-posidcn followed by cyclizadon is a generid method for the synthesis of various heterocycles. When nucleophiles have an electrophilic center, heterocyclic compounds are obtained in one step. Ono and coworkers have used the anion dedved from ethyl isocyanoacetate as the reacdve anion for the preparadon of heterocyclic compounds. The carbanion reacts with various nitroarenes to give isoindoles or pyriirddines depending on the stnicture of nitroarenes fEqs. 9.56 and9.57. The synthesis of pyrroles is discussed in detail in Chapter 10. 

There has been a short review of the oxidative nucleophilic substitution of hydrogen in nitroarenes in which recent results with carbon, nitrogen, and oxygen nucleophiles are summarized and the preferred oxidants are discussed.11 The oxidative substitution of nitroarenes with carbanions of isopropyl phenylacetate in liquid ammonia-KMn04 initially yields products (4) which may suffer hydroxylation at the o -position, and dimeric and trimeric products may be formed by couplings of nitrobenzylic radicals formed during the reaction.12... 

The Barton Zard condensation is one more important and marvelous SnH heterocyclization leading to pyrrole ring annulation to nitroalkenes, nitroarenes or nitrohetarenes on being treated with alkyl isocyanoacetates in the presence of a base (85CC1098, 90T7587). The reaction starts with nucleophilic attack of alkyl isocyanoacetate carbanion 160 ortho to the NCT group of substrate 161. The... 

Oxidative nucleophilic substitution of the hydrogen in nitroarenes with the carbanion of isopropyl phenylacetate using lb gives corresponding isopropyl hydroxyaryl(phenyl)acetates, which is not the case with Bu4N Mn04 or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) oxidants <2005T11952>. 

In a so-called vicarious nucleophilic substitution of hydrogen,75 2,3-diphenylpyrido[2,3-6]-pyrazine is alkylated in the 8-position by [(chloromethyl)sulfonyl]benzene. This reaction proceeds by addition of the carbanion to the electron-deficient ring position of a nitroarene or electrophilic heteroaromatic system, followed by base-induced -elimination of the corresponding hydrogen halide.76,77 As with quinoxalines and naphthyridines, the reaction with pyrido[2,3-6]pyrazines also affords products bisannulated at the pyrazine or the pyridine moiety, depending on the kind of 2/3-substitution (cf. Section 7.2.3.1.2.2.2.). 

Nucleophilic substitution of halogen atoms in highly electrophilic arenes (most often nitroarenes) by carbanions proceeds efficiently under PTC conditions. However, the catalytic process operates only with methynic carbanions, when the products do not possess an acidic hydrogen atom. In the case of methylenic carbanions, introduction of nitroaryl substituents gives products that are much stronger C-H acids thus, they are immediately converted into nitrobenzylic carbanions which, associated with the lipophilic TAA cations of the catalyst, stay in the organic phase. The low nucleophilic activity of these carbanions prevents their further reactions. In this situation the catalytic process is arrested. 

The high effectiveness of PT-catalyzed nucleophilic substitution of halogen atoms in nitroarenes by carbanions is probably connected with the existence of reacting anions in the organic phase in the form of TAA salts and low concentrations of the reacting species. In this situation eventual competing processes in the organic phase are suppressed. 

When analyzing plausible mechanisms of the VNS reactions of nitroarenes with a-chlorocarbanions, one should clarify a few key questions how to proceed the addition and subsequent conversion of adducts and how other substituents may affect both of these steps - rate and orientation of the addition, rate of the elimination, etc. It is well known that nitroarenes are active electron acceptors, whereas carbanions are good electron donors thus, these reactants can enter a single-electron transfer (SET) to form anion radicals of nitroarenes and radicals from carbanions [21, 22]. Further coupling of these electrophilic radicals with nucleophilic anion-radical species could give adducts. This SET pathway, alternative to the direct addition, is often favored by authors and the concept is sometimes abused, see [23] and rebuttal [24]. Nevertheless, numerous observations contradict participation of the SET mechanism in the VNS reactions ... 

The VNS in nitroarenes with carbanions is presented in general in Scheme 7, thus, discussion of the scope and limitations of this reaction should clarify what kind of carbanions (nature of Y, L, and R) and nitroarenes (kind of Z) can enter the reaction. 

Equilibrium of the addition of nucleophiles to nitroarenes is a function of many factors, such as their nucleophilicity, electron deficiency of arenes, and their ability to stabilize adducts, as well as the reaction conditions. Thus, all these parameters are responsible for the feasibility of ONSH with nucleophiles sensitive to oxidation. Of substantial importance is temperature, since, due to the entropy factor, the equilibrium is shifted toward the adducts at a low temperature. For instance, addition of highly nucleophilic carbanion of 2-phenylpropionitrile to moderately active m-chloro nitrobenzene at —70°C in liquid ammonia or DMF/THF proceeds to completion, selectively in the para-position. Further oxidation of the formed adducts with... 

The effect of temperature on the addition equilibrium can, for instance, be observed in the reaction of the carbanion of diethyl benzylphosphonate with 4-fluoronitrobenzene. At low temperature the addition proceeds exclusively at the position 2, and oxidation of the produced adduct affords the product of ONSH. On the other hand, at room or a higher temperature the S Ar of fluorine in the position 4 takes place [76]. Similarly, when the reaction of nitroarenes with the anion of diphenylphosphine is carried out at low temperature in liquid ammonia in the presence of KMn04 diphenyl(nitroaryl)phosphine oxides are formed, as illustrated by the ONSH in 4-fluoronitrobenzene (Scheme 16) [77]. 

The adducts of nitroarenes with various nucleophiles can be oxidized with a few oxidants, and oxygen is probably the most common oxidant, although it has a limited application. It oxidizes adducts resulted from the addition of OH anion to nitroarenes to produce nitrophenols and also adducts of secondary and primary carbanions. Some observations and experiments lead to conclusion that for oxidation by oxygen the anionic adducts should first be deprotonated, so in fact, dianions are oxidized [78]. Oxidation of such adducts with oxygen appears to proceed via an electron transfer. On the other hand, oxidation of the adducts of nitroarenes with ammonia, the Grignard reagents, various carbanions, or diphenylphosphine by action of KMn04 appears to proceed via direct abstraction of the... 

Diarylmethylation of nitroarenes can be performed efficiently via VNS, using carbanions of benzhydryl aryl sulfides [92]. Similarly, the VNS reaction of 4-ethoxy-3-nitropyridine with carbanion of 9-chlorofluorene results in incorporation of the... 

The VNS is the reaction of choice for incorporation of a-sulfonylalkyl substituents into nitroarenes and their heteroanalogues. Particularly accessible and useful are nitroarylmethyl phenyl sulfones and their heteroanalogues that are efficiently produced in the VNS reactions of carbanions of chloromethyl aryl sulfones with a great variety of nitroarenes and nitroheteroarenes. Nitro derivatives of heterocycles, such as pyrrole [54,55], furan [54], thiophene [54], imidazole [106, 112, 113], pyrazole [114], pyridine [57], indole [115], indazole [116, 117], benzimidazole [118], benzotriazole [119], benzofuroxan [120], quinoline [121], and porphyrins [122, 123], have been shown to enter this reaction. 

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